Certain substituted dibenzo diazocines and their preparation



United States Patent 3,243,430 CERTAIN SUBSTITUTED DIBENZQ DIAZOCINES AN EIR PR PABA IQ Werner Metlesics, Clifton, and Leo Henryk Sternbach, Upper Montclair, N.J., assignors to Hoffmann-La Roche Inc. Nutley, N.J., a corporation of New Jersey No Drawing. Filed Mar. 1, 1965, Ser. No. 436,317 19 (Ilaims. (Cl. 260 239) This application is a continuation-in-part of application Serial No. 263,411, filed March 7, 1963, now abandoned.

The present invention relates to diazocine derivatives. More particularly, it relates to substituted diphenyhfibenzo [-b.f] [1,5]diazocines.

The diazocines of the invention have the formula R a N=C RF s R, \czN/ R,

R Rx

I R7 I wherein R through R, are hydrogen, halogen, e.g. F, C1, or Br, lower alkoxy, lower alkylthio, or trifluoromethyl; and R through R; can be the same or different, except that at least one of R through R must be selected from halogen, lower -alkoxy, lower alkylthio or trifluorornethyl; and R through R, are hydrogen, halogen, e.g. F, Cl, or Br, lower alkoxy, lower alkylthio, lower alkyl, or trifluoromethyl and R through R canbe the same or different.

The compounds of Formula I exhibit antigonadotropic, serum cholesterol lowering, and estrogenic activity, and are useful as antigonadotropins, serum cholesterol lowering agents, and estrogens.

Preferred diazocines of the invention have the formula B1 II wherein R R R and R have the meanings given above and wherein at least one of R and R is halogen, tria 'lesterol lowering agent; and 1,7-dichloro 6,,12 diphenyldibenzo[b,f][-l,5]dia;ocine, 2,8 dichloro-fiflZfdiQ-niethoxyphenyl) -dibenzo[b,f],[1,5]diazocine, and 2,8 4 dichloro 6,12di(p-fiuorophenyll dibengo[b,f] 1 51diazocine have marked activity as antigonadotropinsj I The term lower alkyl used in the jspeciii claims is to be understood to meana straighter-branched chain alkyl group having from 1 to 7 c arbonatpinsheg, methyl, ethyl, propyl, butyl, isopropyl, hexyl 'heptyl, etc.

The compounds of Formula I are prepared by treating a substituted aminobenzophenone of the formula I wherein R through R have the meaning given above, in a solvent, in the presence of a Friedel-Crafts catalyst, such as, for example, AlCl TiCl SnCl SbCl B-F etc. Also, combinations of the above catalysts can be employed, for example, BF plus TiCl etc.

The solvent employed in the above reaction is preferably an inerttorganic solvent, for example, an aliphatic or aromatic hydrocarbon solvent, e.g., petroleum ether, benzene, toluene, etc; -a halogenated hydrocarbon, e .g., tetrachl-oroet-hane, chlorobenzene, etc.

The temperature of the reaction is not critical, although temperatures in the range of from about 60 C. to about C. are usually employed. Lower temperatures can be used, although the reaction time will be increased. Also, higher temperatures can be used, although temperatures above which the reactant or the product decompose ho i qu s no b e ployed- Th rea i n time is not critical, although times in the range of thirty minutes to twenty hours are generally employed.

Among the F-riedel-Crafts catalysts suitable for use in the above-described process, BF and TiCl as Well as mixtures of these two are specifically distinguishable owing to the superior yield of product which is obtained when these catalysts are employed.

A r sd P e t o a y n u the se aratist of the compounds of Formula I is to reflux an aminobenzopheno-ne of Formula III in chlorobenzene in the presence of BF TiCl, or arnixture of B F and TiCl Alternatively, the compounds of Formula .I can be Prepared b at a sm qsa of Fauna-lull in a vent in the presence of a strong base catalyst such as, for example, alkali metal hydrides and alkali metal amides, e.g., sodium hydride, sodamide, potassium amide, etcl, alkali m a sx s ea. ofl mmsthqx de PWWSMP butoxide, etc. The preferred base catalysts are sodium hydride and sodamide. Preferred solvents employed in this prbcess aspect of the invention are the inert organic solvents such as, for example, aromatic hydrocarbons, e. g., xylene, toluene, etc., ethers, e.g'., tetrahydrofuran, etc,, and the like. The reactionis conveniently carried out at temperatures in the range of about 60C. to about 160 C. though higher or lower temperatures can also be used.

A preferred method for carrying out the above-described base catalyzed reaction comprises refluxing a soldt 1 f u d bf F u III in stmh drs uran n the presence of sodium hydride.

Other related processes can be employed to form the 4 EXAMPLE 1 Preparation -6J2-diphenyldibenzo ,1] ldiazocine or more of the R groups is nitro (which compounds can 5 232 g (010 m) of ichlormzamino benzophenone is 'P 'obtameid by the above Promsses "P employmg a Start added in small portions to a stirred, cooled suspension of mg t l of Formula HI wherein the 0.10 mole of aluminum chloride in 300 ml. of chlorogroups Intro) can F the correspondfng benzene. After the addition, the mixture is heated, halo denvatlve by reduclpg FQ groups "P ammo whereupon a large quantity of hydrogen chloride evolves by hydmge 1aun d1'aZot1,Z1ng ammo and a dark solution forms. The mixture is refluxed for f w mtmus acid or eqmv a1ent t form 3 hours, then cooled, poured on a sufiicient quantity of diazomum salt; and converting the d1azon1um salt into ice made basic with aqueous sodium hydroxide, and the corresponding halogen substituted eomp Pl tracted with dichloromethane. The extract is washed with known h by a Sandmeyer Teacuon or a same water and dried over anhydrous sodium sulfate. The reaction solvent is removed under vacuum giving a residue which Hence the mm) mtfirmedlates of the Invention have crystallizes upon addition of ethanol. The crystalline the formula residue is recrystallized from a mixture of dichlorometh- 14 ane and ethanol to give 2,8-dichloro-6,12-diphenyldibenzo [b,f] [1,5]diazocine in the form of yellow prisms, having R13 a melting point of 2l5217 C.

R12 EXAMPLE 2 (L f? Preparation of 2,8-dz'nirr0-6,l2-diphenyldlbenzo RP N= R l jl [1,5]d1azoc1ne The procedure of example 1 is followed except that R1o Rs 12.1 g. (0.05 m.) of 5-nitro-2-aminobenzophenone is em- C=N I ployed together with 0.05 m. of aluminum chloride and R11 Rs 170 ml. of chlorobenzene. The mixture is refluxed for 2 hours and 45 minutes, and after work up as in Example 1, 2,8 dinitro 6,l2-diphenyl-dibenzo[b,f] [1,5 ]diazocine having a melting point of 291294 C. is obtained.

I R IV EXAMPLE 3 wherein R R R and R are hydrogen, halogen, e.g. The compounds given in the table below are all pre- F, C1 or Br, lower alkoxy, lower alky-lthio, trifiuorornethyl pared by the following procedure: or nitro, except that at least one of these groups must be To a 2-aminobenzophenone of Formula III wherein other than hydrogen, and R R and R are hydrogen, the R groups have the meaning given in Table I below, halogen, e.g. F, C1 or Br, lower alk-oxy, lower alkylthio, 4.0 dissolved in chlorobenzene, is added boron fluoride ethyl lower alkyl, trifluoromethyl, or nit-r-o, wherein at least ether and the resulting solution refluxed for the time inone of the R through R groups is nitro. dicate-d in the table. After cooling, the solution is diluted The amino intermediates are identical with the above with dichloromethane and washed with aqueous sodium except that amino is present in place of nitro. hydroxide. Evaporation in vacuo gives a crystalline The invention will be better understood by reference to residue which, upon recrystallization from a mixture of the following examples, which are given for illustration dichloromethane and alcohol, yields yellow prisms havpurposes only and are not meant to limit the invention. ing the melting point shown in Table I below:

TABLE I Quantity of 2- Catalyst, Z-aminobenzophenone aminohenzo- BFwEtgO Vol. of (all R groups not given phenone chloroben- Reaction Product M.P., below are hydrogen) zene in mi. time in hrs. C.

G. Moles Ml. Moles R3=Cl I 23.2 0.10 1.3 0.01 100 16 2,8-dich10r0-6,12-diphenyldibenzo[b,f] [1,5] 01- 215-217 fl-ZDCIIIG. R3=F 0.5 0.0023 0.05 0.0004 15 17 2,8-diflu0ro-6,12-diphenyldibenzo [15,0 [1,5] dl- 187-489 81001116. Ra=Br 6.9 0.025 0.4 0. 003 25 16 2,8-dib r0m0'6,IZ-diphenyldibenzo [b,r] [1,5] di- 229-232 2.2001118. R3=O CHK 3.9 0.018 0.2 0.0015 80 6 2.2gdimethoxy-6,IZ-diphenyldibenzo [M] [1,5] 202-204 19. 001118. a= R5=F 5.9 0.02 0-5 0- 0039 20 16 2,8-diloromo-6,12-bis(0-fluorophenyl)-dibenzo 230-232 V [b,f] [1,5] diazocine. R3=C1, R5=OCH3 1.0 0.0038 0.1 0.0008 15 16 2,fii;li]cl[iil%rlo(-lfi ,l2-biis(o-mcthoxyphenyl)-dibenz0 256-258 I 1 Rs= 1, Ra=C1 13-3 0.05 0.7 0. 0055 16 2,8-dichloro-6, 1 2 l%i s m-chlorophenyl)-dibenzo 189-192 (l il ,5] diazocine. 2.7 0.011 0.25 0.0020 15 16 2,8-dichl0z0-6,12-bis(p-fluorophenyD-dibenzo 250-252 [b,t'] [1,5] diazoeine. 46.4 0.20 2.6 0.020 200 16 3,9-diehloro-6,lwdiphenyldibenzo [b,f] [1,5] dl- 253-264 azocme. 11.6 0.05 0.65 0.005 50 16 1,7-dichl0r0-6,12-diphenyldibenz0 [b,f] [1,5] di- 242-243 azocine. Rz=CL R3=C1 8.0 0. 03 0.4 0.003 30 16 2,3,8,9-tetrachloro-6,IZ-diphenyldibenzo [b,f] 348-350 [1,5] diazocine.

EXAMPLE. 4

The procedure of Example 3 is carried out with the compounds given in Tabl'e'i except that xylene is used as solvent in place of chlorobenzene. The time required (usually 4-6 hours) for the reaction is indicated by the amount of water collected in a Dean Stark trap.

EXAMPLE 5 The procedure of Example 3 is carried out except that 6 low prisms which" after recrystallization from a' mixture of dichloromethane and ether melts at: 2682'7.0. After resolidifioation: the. melting. point is. 278-280", probably dile-torditnorphism.

(:B.) Preparation 0 2,8-diflu0r0-6-,1Z-diplienyldibenzo [b,]],[ 1.,5]dia zOcine A solution of 114* g. (0102 moles) of sodium nitrite in ml. of water is added dropwise to a solution-of 3.9 g.

titanium tetrachloride is employed in place of boron 10 (0.01 mole) of 2,8-diamino-6.12-diphenyldibenzo[b,f]

fluoride ethyl ether.

[.l ijdiazocine in 125 ml.. ofca. 015- N1 hydrochloric acid.

TABLE II Quantity of 2- Catalyst, 2-ammobenzophenone aminobenzo- T101. V01. of. (all R groups not given phenone; ohlorobeu- Reaction Product. 1\ 1P., below are hydrogen) zene in mi. timein hrs. C.

G. Moles lifii Moles R3=Ol 23.2 0.10 5.2 0.047 100 16. .f2,8-dichloro-S;12-dlphenyldibenzo, [b,t'] [135]: di. l215-217 azocme. 10. 8- 0.05 2.6 0. 024 50 16 j 2;8 difluoro 6;12-diphenyldlbenzo' [b ,t] [1,5] di- 187-189 azoolne. 13. 3 0.05 2.2 0.02 150 2 2,8ebis(trifluoromethyD-G,12-diphenyldibenzo- 202 -205 [b,f] [1,5] diazochie. I Ra R5=Cl 13.3 0.05 2.7 0.025 50 165 2,8ljadhel[i%osrloatt,l2 b is(o-chlorophenyl)-dibenz0. .211-213 iazocme. Ra=Cl, R =CH 2.4 i 0.01 0.4 0.004 10. 16' 2,8-dicliloro-6;12=di-o-tolyldibenzo [b',t] [1,5] dl- 185-187 azocine. R1=NOZ 24.2 0.10 5.8 0.053 100 16. 2,8-dinitro-6,-12-diphenyldibenzo[b,i][1 51415 291-294 azoeme: Ra=SCzH 5:4 i 0.02 1.1 05010 j 16. '2,%bis(ethylthio) 6;12-dipheny1dibenzo*[bj][1,5] 123-125 i iazocme.

*Benzeue was used in this ease instead of chlorobenzene.

EXAMPLE 6' The procedureemployed' isidentical to that given for Example 3 except that amixture of boron-fluoride ethyl ether and titanium tetrachloride is used as catalyst.- The results are given in Table III below.

TABLE III Quantity of 2ami- 2-aminobenzophenone nobenzophenone VOL 0Q. Be s c (all R groups not given Catalysts in 0511501 111 I tlme hrs Product M.P., C

below are hydrogen) 7 ml. ml. G. Moles h i RFC] 5; 8 0.025 16 ehtg gg s g .1 (hp enyldlbenzo .01 5] 182 3 24,8,I0etetrabromo-6d2-di hen ldibenzo- 271-273 R1=R =Br 18.0 0. 05 50 I 16 1 110mm] dimming p y 1 2,3,4,7,8,9,10-octachloro-6 12-dipl1eny1di- 336-338 R1=R2=R3= l=C1 6.7 v 0. 02 -c 16 benzo'-[b,f][1',5] diazocinei EXAMPLE 7 It is dried and distilled in a bulb tube (0.2 mm., bath temperature 250 C.) to-give a yellow glass-which crystallizes Preparation of fi ggg 'g i on scratching. Recrystallization from methanol gives EXAMPLE 8 (A) Preparation 0 2,8-diamin0-6, 1Z-diphenyldibenzo [b,f] [1,5] diazocine A solution of 2.2 g. (0.005 mole) of 2,8-dinitro-6,12- diphenyldibenzo[b,f][1,5]diazocine in 200 ml. of tetrahydrofuran is hydrogenated at 25 and atmospheri pressure using ca. 0.5 g. of Raney nickel as catalyst After 1 hour the uptake of hydrogen was 630 ml- (ca. 0.026 mole) and the hydrogen absorption stops. The catalyst is separated by filtration and; the solution is evaporated in vacuo. The residue crystallizes on addition ofether to form yelcrystals melting at 185-187? The product is identical to that obtained by the method described in Example 3'.

(Q) Preparation of 5,3--dichZora-2-amin0benzophen0ne To 66.5 g. of p-chloroaniline is added slowly with stir-ring g. of m-chlorobenzoyl chloride. The temperature is raised to 65 C. to complete the evolution of I-IClgas and the temperature is then raised to 200 C. whereupon 66.5 g. ofzinc chloride is added. Stirring is continued and the temperature is raised to 230-240" C. and maintaned at this temperature for 2 hours. The reaction mixture is then poured onto a mixture of 1 l. of 0.5 n-HCl and 2 kg. of ice. The resulting. crystalline mass-is air dried andthen suspended in 500 ml. of 0.5 n-HCl' and refluxed; The-solid mate-rial melts to an oil and the acidic aqueous phase is removed by decantation. This process of treating the solid materialiwith 500 ml. of 0.5 HCl and refluxing is repeated two more times. and. the solid. material then treated. with 1. l. of Water. The residue is then refluxed with 600 ml. of 85. percent H 80 at a temperature of -150 C. for 1 /2 hours. and; then poured onto ice. The mixture is then extracted with 6 l. of ether (portion wise) and the aqueous phase discarded; The ether layer is then washed with 0.5 n-HCl and then 3 times, each time with 1 l. of n-NaOH, concentrated, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to yield 5,3 dichloro 2 aminoben'zophenone. Recrystallization from ethyl alcohol yields a product melting at 107-109 C.

The preparation of 2-benzoyl-3,4,5,6-tetrachloroanilirie is given hereinafter for purpose of completeness, although it is to be understood that this compound and the process for its preparation do not comprise part of the invention disclosed and claimed herein.

(D) Preparation of 2-benz0yl-3,4,5,6-tetrachloroaniline -zoyl-3,4,5,6=tetrachlorobenzoyl chloride-separates. After chilling in an ice bath for an hour, the crystals are filtered off and washed with petroleum ether. The product has a melting point of l84185 C.

75 g. of 2-benzoyl-3,4,5 ,6-tetrachlorobenzoy1 chloride is stirred for 18 hours in a mixture of 4 l. of ethyl alcohol and 4 l. of concentrated ammonium hydroxide. The solid is then filtered off, the filtrate diluted with 41. of water and the precipitate that forms added to the originally obtained filter cake. The filter cake, which is 2-benzoyl-3,4,5,6- tetrachlorobenzamide, after washing well with water, melts at 260-265 C. After recrystallization from 8 l. of 60 percent aqueous alcohol, crystalline product is obtained melting at 270-274 C. Upon further recrystallization, the melting point rises to 272274 C.

In a flask equipped with a stirrer, thermometer and reflux condenser is placed 58 g. of 2-benzoyl-3,4,5,6-tetrachlorobenzamide, 58 g. of potassium hydroxide dissolved in 2800 ml. of methanol, and 105 ml. of sodium hypochlorite solution, assaying 16.8 percent active chlorine.

The stirred suspension is warmed to 45-50 C., and maintained at this temperature for about 10 minutes. Then the solution is refluxed for 1 hour, 58 ml. of glacial acetic acid is added, the condenser is changed for downward distillation, and 2 1. of methanol distilled off. One 1. of water is added to the residue and the mixture is chilled. The resulting yellow solid is filtered off, washed well with water, and dried in vacuo over calcium chloride to yield 2-carbomethoxyamino-3,4,5,6 tetrachlorobenzophenone of melting point 200-204 C. Upon recrystallization from acetic acid, the product is obtained in the form of bright yellow needles melting at 207-208 C.

61 g. of 2-carbomethoxyamino-3,4,5,G-tetrachlorobenzophenone is added to a solution of 183 g. of potassium hydroxide in 2 l. of methanol and 1 l. of water in a flask equipped with a stirrer and condenser set for downward distillation. The solution is warmed, methanol distills out, anda crystalline yellow precipitate forms. Distiflation is continued until the vapor temperature reaches 98? C. The residue isthen chilled and the yellow precipitate is filtered off and washed free of alkali with water.

The dry 2-benzoyl-3,4,5,6-tetrachloroaniline melts at 172l77 C. Upon recrystallization from ethanol, the .product is obtained as bright lemon-yellow crystals melting at l73-174 C.

EXAMPLE .9.

'Based catalyzed preparation of 2,8-dichlbr0-6J2-diphenyl dibenz0[b,f] [1,5]diazoci'ne v To a solution of 4.6 g. (0.02 mole) of Z-amino-S-chlorobenzophenone in 40 ml. of tetrahydrofu'ran was added .1.2 g. (0.025 mole) of a 50 percent suspension of'sodium hydride in mineral oil. The mixture was heated to reflux for 6 hours andcooled. Methanol was added and the solution was concentrated on a steam bath. The crystals which precipitated melted at 2162l8 and were identified as 2,8-dichloro-6,12-diphenyl-dibenzo[b,f] [1,5 [diazocine. I

We claim; 1. A compound of the formula wherein R R R and R are selected from thegroup consisting of hydrogen, halogen, lower alkoxy, lower alkylthio and trifluoromethyl, except that at least one of R R R and R is other than hydrogen; and R R and R are seelcted from the group consisting of hydrogen,

[1,5] diazocine.

halogen, lower alkoxy, lower alkylthio, lower alkyl and wherein R and R are selected from the group consisting of hydrogen, halogen, lower'alkoxy, lower alkylthio and trifluoromethyl, except that atleast one of R and R is other than hydrogen, and R and RIP; are selected from the group consisting of hydrogen, halogen, lower alkoxy,

lower alkylthio, lower alkyl and trifluoromethyl.

3. 2,8 dichloro-6,l2-diphenyldibenzo[b,f][1,5] diazocine.

4. 2,8 dibromo-6,12-diphenyldibeuzo [b,f] [1,5] diazocine.

5. 2,8 bis(trifl uoromethyl)-o,l2-diphenyldibenzo[b,f]

' 6. 2,8 -.dichloro 6 12 bis( o-methoxyphenyl)dibenzo [b,f] [1,5 diazocine. "1

[1,5 diazocine.

8. 1,7 dichloro 6,lZ-diphenyldibenzo [1,5 diazo- 9; 2,8 l dichloro-6,12-di-o-tolyldibenz o at t 1,5 1 diazo- 10. A compound having the formula Ri2 s I l n N=C RP 10 10 \C=N/ 1 R11 R8 wherein R through R are selected from the group consisting of hydrogen, halogen, lower alkoXy, lower alkylthio, trifluoromethyl, nitro and amino; and R through R are selected from the group consisting of hydrogen, halogen, lower alkoxy, lower alkylthio, lower alkyl, trifluoromethyl, nitro and amino; wherein at least one of R through R is other than hydrogen, and wherein at least one of R through R is selected from the group consisting of nitro and amino.

11. 2,8 dinitro 6,12 diphenyldibenzo[b,f][1,5] diazocine.

12. 2,8 dinitro 6,12 diphenyldibenzo[b,f][1,5] diazocine.

13. A process for preparing a compound of the formula wherein R R R and R are selected from the group consisting of hydrogen, halogen, lower alkoxy, lower alkylthio and trifluoromethyl, except that at least one of R R R or R is other than hydrogen; and R R and R are selected from the group consisting of hydrogen, halogen, lower alkoxy, lower alkylthio, lower alkyl and trifluoromethyl, comprising the steps of reacting a compound to the formula wherein R through R have the meaning given above, in a solvent in the presence of a Friedel-Crafts catalyst.

14. A process according to claim 13 wherein said solvent is selected from the group consisting of hydrocarbon and halogenated hydrocarbon solvents.

15. A process according to claim 13 wherein the reaction temperature is selected from the range of about 60 to about C.

16. A process according to claim 13 wherein the catalyst is a compound selected from the group consisting of BF TiCl and mixtures of B1 and TiCl 17. A process according to claim 13 wherein polyphosphoric acid is employed in place of the Friedel-Crafts catalyst.

18. A process for preparing a compound of the formula wherein R R R and R are selected from the group consisting of hydrogen, halogen, lower alkoxy, lower alkylthio and trifluoromethyl, except that at least one of R R R or R is other than hydrogen; and R R and R are selected from the group consisting of hydrogen, halogen, lower alkoxy, lower =alkylthio, lower alkyl and trifluoromethyl, comprising the steps of reacting a compound of the formula wherein R through R; have the meaning given above, in a solvent in the presence of a strong base catalyst selected from the group consisting of alkali metal hydrides, alkali metal amides and alkali metal alkoxides.

19. The process of claim 18 wherein the strong base is a member selected from the group consisting of sodium hydride and sodamide.

References Cited by the Examiner Hickenbottom: Reactions of Organic Compounds, London (1948), pages 314-316, 343-350, and 372*377.

Patent Journal, Republic of South Africa, vol. 1, page 30 (in English), June 21, 1961.

HENRY R. JILES, Primary Examiner.. ALTON D. ROLLINS, Assistant Examiner. 

1. A COMPOUND OF THE FORMULA
 10. A COMPOUND HAVING A FORMULA
 13. A PROCESS FOR PREPARING A COMPOUND OF THE FORMULA 